To minimize immediate and late toxic effects of radiation to normal tissue, most often radiation is administered through multiple treatment fields. Smaller fractions of daily prescribed dose of radiation are given to each of the treatment fields. The radiation from such multiple fields converges at the tumor site to give the daily fractionated dose of radiation. The sum of the radiation dose from each of such smaller fields makes the prescribed daily dose of radiation to the tumor.
Radiating a tumor by multiple fields with a single accelerator is an interrupted daily fractionated radiation of the tumor. After setting up a patient in treatment position on the treatment table to treat the first field and after its various checks and verifications and treating, the gantry with the treatment head has to be rotated to bring it to the next treatment field. It follows a number of checks and verifications for the accuracy of this second treatment field's set up before its treatment and subsequent treatment. If it were a four fields daily fractionated radiation therapy, then this process of rotating the gantry with the treatment head from one position to the other to bring the radiation beam from each of those fields directed towards the tumor and checking and verification for the accuracy of each field's set up before radiating is repeated four times. If it were a six or eight field daily fractionated radiation therapy set up, then this process of field set up on the patient for radiation and checking for its accuracy before each field's radiation is repeated six or eight times respectively. After treating one field, the accelerator room with the patient positioned on the treatment table is opened to enter the room, to check the patient's condition, to rotate the gantry with the treatment head, to check the field set up and if the patient has moved then to readjust the treatment field set up and all other parameters of treatment before delivery of radiation to each fields. The patient setup has to be in conformity with the treatment planning. In some instances these process can take just a few minutes as in the case of a small segmented arc treatment. Most often it takes several minutes to deliver the daily prescribed dose to the tumor through multiple fields. Hence the present daily fractionated radiation therapy is a daily subfractionated radiation therapy that lasts from a few minutes to much longer periods.
There are computer controlled patient set up and treatment methods that could reduce the time required for the delivery of daily fractionated radiation therapy; still it is a lengthy interrupted, subfractionated daily radiation therapy. Moreover, all the treatment plans that look as good in the computer color screen may not be as good and accurate on the patient. The patients do move, especially when they are very sick and hence the need for verifications of each fields set up on the patient before delivery of radiation to a field of treatment.
As an example, it takes about 10 minutes to complete a computer controlled patient setup and treatment of a 6 segmented prostate cancer 3-D conformal radiation therapy; 6 minutes for the patient set up and 4 minutes for the treatment. The corresponding time to treat the prostate with blocks is 16 minutes. A six field's treatment by the present advanced segmental treatment delivering 180 to 200 cGy is equivalent to 30-33 cGy if these segments are not intensity modulated. Since this total dose of 180-200 cGy is delivered from multiple fields with lapsed time for setup and activation of the accelerator and delivery of radiation, it is in effect a subfractionated radiation therapy within the conventional daily 180-200 cGy fractionated radiation therapy.
It is also the case for different forms of intensity modulated radiation therapy (IMRT). The IMRT by multisegmented static fields, by dynamic IMRT, intensity modulated arch therapy all are subfractionated daily radiation therapy. Even the daily slice per slice treatment of a say 10×10 cm filed with the tomotherapy is a subfractionated radiation therapy. Based upon the slice thickness ranging from 0.5 to 5 cm that is used to complete daily radiation by tomotherapy, the time to complete the treatment is about 5 to 10 minutes. Hence the daily conventional and the 3-D conformal radiation therapy, the IMRT and the tomotherapy all are daily subfractionated radiation therapy within the daily-fractionated radiation therapy. Radiobiologically, its tumor cell kill is poor since it is dominated by alphaD1. It is an inefficient method of radiation therapy.
In photon and electron beam radiation therapy, the indirect action of radiation on DNA predominates. The free hydroxyl radical (OH.) reacts with DNA to produce the DNA damage. The lifetime of the OH radicals outside the cell is 10−10 seconds and inside the cell; it is 10−9 seconds. The DNA radicals formed by the direct (high LET) or indirect action (OH.) have a lifetime of 10−5 seconds. Although the effects of such ionization of the cells may last for hours, days or years depending on the consequences involved, it is only a relative long term effect than those associated with the immediate cell kill effects from free OH radicals produced by radiation.
On the other hand if 180-200 cGy daily fractionated radiation is delivered to the tumor by radiating all the treatment fields simultaneously, all filed synchronous radiation therapy (AFSRT), and each treatment field is treated with a separate accelerator, the above disadvantages of the subfractionated daily radiation therapy is eliminated. There are many radiobiological advantages for AFSRT as compared to the present conventional sequential radiation therapy of each fields including in 3-D conformal radiation therapy (3-DCRT) and IMRT. Furthermore, the radiation intensity of each accelerator treating each field is controlled to facilitate efficient IMRT. The accelerator that delivers radiation to a region that needs a higher dose rate is tuned to a higher dose rate and higher energy and the region that needs a lower dose, the dose rate is tuned to a lower energy and lower dose rate. The tumor is treated in 3-D conformity. Hence it is a 3-D conformal all filed synchronous intensity modulated radiation therapy (3-DC-AFS-IMRT) with multiple accelerators.
The AFSRT, AFS-3-DCRT, and 3-DC-AFS-IMRT, are much different than the present radiation therapy systems. In present IMRT systems increased monitor units and radiation filters are used for intensity modulation of the radiating beam. Higher the monitor units is used to radiate a filed, higher its leakage and scattered radiation and the total radiation received by the normal tissue surrounding the tumor and the tissue through which the radiating beam passes through towards the tumor site. This causes much more late complications from radiation therapy and second primary tumors as a result of earlier radiation to the primary tumor.
There are significant radiobiological difference between the interrupted subfractionated 30-33 cGy per field to give the total daily dose of 180-200 cGy and the simultaneous delivery 180-200-cGy to a tumor. In the latter instance, the daily subfractionated radiation therapy is eliminated. By doing so, the total cumulative radiation dose required to cure and or control a tumor is decreased. Most importantly, the patient comfort is increased significantly. To place a sick patient on a hard treatment table and to except not to make any movements regardless of the patient's discomfort is an unusual physician's prescription due to its need and circumstances.
The shape of cell survival curves for mammalian cells under photon or electron beams has an initial linear slope followed by a shoulder, (• D1) and a straight portion, the βD2. The initial linear slope and shoulder is associated DNA breaks induced by the same electron at low dose rates while the steeper portion of the cell survival cure represents the two DNA breaks caused by two separate electrons. Within the daily fractionated radiation with subfractionation daily setup and multiple field interrupted treatment as described above with about 30 cGy dose rate to the tumor at any one time is dominated by the alphaDi.
On the other hand, if the entire daily fractionated dose is delivered to the tumor simultaneously with multiple accelerators, the dose rate at the tumor will be four times higher, namely 180 to 200 cGy and hence much increased chances of inducing βD2 like DNA breaks with multiple electrons.
In clinical radiation therapy with photons and electrons, the AFSRT of a tumor with multiple accelerators could lead to much improved tumor control probability. Theoretically one could foresee a five fold improvement by such treatment. In brief, its radiobiological effects in clinical radiation therapy such as on lethal, sublethal and potentially lethal DNA damage and repair associated tumor cure with lesser toxicity to normal tissue have great significance. Because of the simultaneous radiation to all the treatment fields and its higher dose rate effects, the total treatment dose for the entire course of treatment of a patient could be reduced. In this instance, the dependence on isoeffective radiation dose on duration and number of fractionation, the time and radiation dose relationship has changed from all forms of present conventional daily fractionated radiation therapy including the 3-DCRT. The 3-DC-AFS-IMRT has a higher tumor cure probability at lower total tumor dose.
In those patients surviving longer after radiation therapy by IMRT, the risk to develop second malignancies is increased by 0.5% than when they are treated by 3-DCRT. It is due to a larger volume of normal tissue is radiated to a lower dose by IMRT as compared to 3DCRT. In addition there is increased leakage and scattered radiation from increased monitor units used in IMRT. Due to beam modulation with a series of leaf sequences in IMRT the ratio of monitor units used are increased by a factor of 2 to 3. It is estimated that it causes an additional 0.25% second malignancies in patients surviving longer after IMRT. Thus there is an increase of 0.75% second malignancies after IMRT as compared to 3-DCRT. It is about twice the incidence of second malignancies observed with conventional radiation therapy (Hall, E. J. and Wuu, C. S. Radiation Induced Second Cancers: the Impact of 3-DCRT and IMRT, Int. J. Radiation Oncology, Biol. Phys., 56, p 83-88, 2003).
The increased risk for second malignancies is reduced by 3-DC-AFS-IMRT with multiple accelerators. 3-DC-AFS-IMRT is like 3-DCRT. The 3-DC-AFS-IMRT with multiple accelerators facilitates lower monitor units set up radiation to deliver the same tumor dose as in IMRT but without sacrificing the advantages of IMRT. The leakage and scattered radiation of IMRT is decreased. In this 3-DC-AFS-IMRT, semi automated blocks made of tungsten powder mixture or melted Cerrobend are used to make custom shaped treatment fields that are in conformity with the anatomy of the tumor and to exclude its surrounding normal tissue. This reduces about 2 to 4 times the scattered and leakage radiation as compared with the conventional IMRT with multileaf collimators. In 3-DC-AFS-IMRT with multiple accelerators and semi-automated custom blocks are made with tungsten powder mixture or melted Cerrobend.
Within this custom shaped larger treatment filed, dynamic variable smaller field size adjusting movements of the secondary collimators is made to make multiple smaller fields. It is combined with selective dose rate and energy adjustments of the accelerator. This provides intensity modulated beam delivery like in dynamic beam delivery with MLC; however it is with dynamic movements of the secondary collimators to make multiple smaller fields within the larger field of each beam directions. It does not involve partial absorption of the beam for intensity modulation. This provides a smoothly variable intensity profile as needed for the IMRT. In effect, it is a single field treatment and the monitor units needed to treat the whole field is the same as in conventional radiation therapy. Hence it reduces the monitor units needed to treat a filed as compared to the segmented, static multiple small fields within a larger filed treatment with MLC.
It also differs from the intensity modulating percent filtration of the beam as with dynamic beam delivery with MLC. Thus this field adjusting dynamic movement of the secondary collimator combined with dose rate and energy adjustments of the accelerator allows treating the tumor with lesser monitor units as compared to doing so with the MLC. Hence it generates lesser scatter and leakage radiation as compared to IMRT with MLC. The intensity of the radiation to a selected field is also modulated by selection of desired dose rates from each of the accelerators.
The higher monitor units used with conventional IMRT with MLC generates higher scattered and leakage radiation that causes increased radiation dose to normal tissue. The dynamic secondary collimator's field adjustments within a larger treatment field for each beam's intensity modulation combined with accelerator's dose rate and energy adjustments along with controlled speed of the secondary collimator's field size adjusting movements as in this invention enables to treat each of the treatment setup fields with much lesser monitor units as compared to doing so with MLC. It reduces the short term and long term complications of radiation therapy. It helps to eliminate or decrease the estimated incidence of additional 0.25% second malignancies among long term survivors as when treated by the present IMRT systems. It is further explained below by analysis of cancer incidence among the Japanese A-bomb survivors.
Data from Japanese A-bomb survivors who had acute whole body exposure of 200 cGy shows a four fold increase in bladder cancer in later life. Patients who survive 10 years or more after 48-67 Gy radiation treatment for prostate cancer have a relative risk (RR) of 1.8 for bladder cancer. Similarly, patients who survive 10 years or more after 30-80 Gy radiation treatment for cervical cancer have a RR of 5 for bladder cancer. This indicates that there is no difference in RR for bladder cancer over the dose range of 2 to 80 Gy.
In Japanese A-bomb survivors, the risk to develop solid tumors is linear up to 200 cGy acute exposure. The International Commission on Radiation Protection (ICRP) recommends the dose rate effectiveness factor (DREF) of 2 for low dose, low dose rate exposure. Allowing DREF as 2 and extrapolating from the Japanese A-Bomb survivors, the risk to develop solid tumors after fractionated radiation therapy could be considered as linear up to 400 cGy. (Hall, E. J. and Wuu, C. S. Radiation Induced Second Cancers: the Impact of 3D-CRT and IMRT, Int. J. Radiation Oncology, Biol. Phys., 56, p 83-88, 2003).
3-DC-AFSRT-IMRT with multiple accelerators is also advantageous in combined radiation and chemotherapy for cancer. In comparison with most chemotherapeutic agents, radiation is a weak carcinogen. In general, the chemotherapeutic agents produce more DNA lesions than the radiation; though it varies widely form one chemotherapeutic drug to another (Hall, E. J., Chemotherapeutic Agents from the Perspective of the Radiation Biologist, in Radiobiology for the Radiologist, Fifth Edition, p. 470-494, Lippencott, William and Wilkins, 2000). Concomitant radiation and chemotherapy is the choice of treatment for many solid tumors. Hence the carcinogenic effects of increased leakage and scattered radiation of IMRT has more clinical significance when combined radiation and chemotherapy is administered.
IMRT combined with chemotherapy with drugs like etoposide for carcinoma of the lung is a common clinical practice. Etoposide is known to cause secondary acute non-lymphocytic leukemia (ANLL). It is associated with translocation in band 11q23 and MLL gene rearrangement. It has a short latency period of 2-4 years and has no effective traditional chemotherapy. (Smith M. A., Rubenstein L, Anderson, J. R., Secondary Leukemia or mylodysplastic Syndrome after Treatment with epipodophyllotoxins, J. Clin Oncol. 17, p 569, 1999) In this scenario, an increase in leakage and scattered radiation to the normal tissue form IMRT is not a desirable option. To avoid later higher chances for the development of a second primary tumor, the dose to normal tissue needs to be kept as minimum as is possible.
Radiation Therapy Machine with Multiple Accelerators Mounted on to a Modified Conventional Accelerator's Gantry for Synchronous Treatment of all the Treatment Fields
In this instance, parts of present conventional divergent beam medical linear accelerator is used to make a synchronous all field radiation therapy machine with multiple accelerator units. It is combined with a kV CT for IGRT. The main gantry of a conventional medical accelerator is modified to hold multiple accelerators with the treatment head and accessory holder. Extensions to the gantry are made to attach additional accelerators and the treatment head with the accessory holder. Each of the accelerator units contains all the parts of a conventional medical linear accelerator namely the accelerator waveguide, treatment head with the bending magnet, target, dose monitors and other related accessories and the accessory holder. Alternatively, split electron beams from a racetrack microtron or a simpler microtron is guided into each smaller medical linear accelerators of the multiple accelerator incorporated radiation therapy system of this invention.
This accelerator system is placed behind a kV CT. With the extension attached to the main rotating gantry of a conventional medical linear accelerator. When a combination of four accelerators is attached to a partially rotating gantry at 90° apart, a 45° forward or backward rotation is sufficient to enable a combined 360° gantry rotation. The 45° gantry rotation is easier for this multi accelerator system than a complete 360° rotation. However, these gantries can make more than 45° rotations. It allows treating a patient from any desirable angles. The extension gantry is attached horizontally when the main gantry is perpendicular, at 0°. Each of these gantries holds two medical accelerators, one at each ends. These gantries with the treatment heads and accessory holders are made to rotate around the CT's table top with flat table top insert when they are extended towards the accelerator system through the CT-gantry's opening. The accelerator components including the electron accelerating waveguide, bending magnet, field defining primary and secondary collimators, dose monitors and the accessory mount that holds the custom shaped blocks all are the same as in a conventional medical linear accelerator. Likewise the electric and electronic components including the thyrotron, power supplies, cooling systems, vacuum pumps and other accessories including the dose monitors are all the same as in a conventional medical linear accelerator. It is an adaptation of the conventional medical linear accelerator into a multi-medical linear accelerator system for simultaneous treatment of all the treatment fields at one time to avoid interrupted subfractionated daily fractionated radiation therapy. Like in a conventional medical accelerator, both gantries are isocentrically mounted but with the capability to extend individual accelerators plus or minus 20 cm to make adjustments for the SSD method of treatment. To make this extension or retraction of the accelerator unit with the treatment head, each accelerator with its treatment head is made to slide on a gantry extending and retracting teethed bar that engage with the teethed slots in a fixed second bar within the gantry. When the accelerators are in isocentric position, isocentric SAD and rotational treatment methods are possible. When the treatment heads on the gantry are moved to adjust the SSD, the SSD method of treatment is feasible. To maintain the treatment position of the patient placed on the CT's table top with the flat table top insert after the kV CT imaging for IGRT is done no additional CT-table positional changes are made during the radiation therapy.
The first accelerator unit is mounted onto the gantry as in a conventional medical linear accelerator. The second accelerator is mounted at the end of this main gantry where the counterweight or a beam shield is attached to a conventional medical accelerator's gantry. In this instance, the counter weight or the beam shield is removed and in its place the second accelerator with its treatment head and the accessory holder are mounted. In addition, modifications are made for moving the gantry extending and retracting teethed bar. It is made to slide on a fixed second bar with a motor driven drive mechanism. Without the gantry's extension or retraction the accelerator treatment heads are at isocenter distance of 100 cm. Forward or backward rotation of one of the engaging teeth and slot on these bars moves the accelerator and the treatment head 1 cm forward or backward. The maximum forward or backward travel distance of the sliding teethed bar on the fixed second bar is limited to 20 cm. A 20 cm forward extension or 20 cm backward retraction of the sliding gantry extending and retracting teethed bar with the accelerator head and the accessory mount increases the SSD to 120 cm or decreases to SSD to 80 cm. If a lesser forward or backward extension or retraction is elected then these SSD distances will vary accordingly. This variable SSD setup capability along with the capability to select the isocenter distance of 100 cm allows treating a patient either by SSD method or by SAD method. A bellowed connection of the gantry between its cut portions facilitates these extending and retracting movements of the accelerator's treatment head with the accessory mount.
As an alternative to the above partially or fully rotating gantry with multiple accelerators, non-rotating gantry with multiple accelerators capable of deflection of the electron beam exiting from the accelerator's waveguide by deflection magnets before it strikes onto the target to produce the photon beam is used to make effective rotational beam for the treatment of multiple fields from multiple beam directions. In this instance, the gantry with multiple accelerators does not rotate. In the case of a radiation therapy machine with four accelerator combination, the accelerators are attached to the gantry at 90° apart, at 0, 90, 180 and 270°. The microwave power to the accelerating wave guide is supplied from shared microwave power generating magnetrons or klystrons by splitting the microwave power from the source and conducting it through microwave transmitting tubes in the gantry and the gantry extensions holding the accelerators. These accelerator units are made to deliver radiation from 0 to 45 and 0 to 315°, from 90° to 135° and 45°, from 180° to 225° and 135°, and from 270° to 315° and 225° ranges by deflection of the electron beam exiting from the accelerator waveguide by deflection magnets before it strikes onto the target to produce the photon beam. If a field is to be treated from 45° angle ranges, then the electron beam exiting from the waveguide of the accelerators either at 0° or at 90° is deflected within this 45° range of treatment directions. If one of the beams is elected as from 45° angles, the electron beam from the 0° accelerator is deflected 45°+, that is in clockwise direction or the electron beam from the 90° accelerator is deflected −45°−, which is in anticlockwise direction. If one of the treatment angles is elected as 200, the electron beam from the 0° accelerator is deflected 20°+, that is in clockwise direction. If one of the treatment angles is elected as 340° angles, the electron beam from the 0° accelerator is deflected 20°−, that is in anticlockwise direction. In other words the beam directions from each of the accelerators can be adjusted 45° either forward or backward by electronic scanning of the exit beam from the accelerator's waveguide. With four accelerators, all mounted to a fixed gantry and with such forward or backward scanning of the electron beam exiting from the waveguide enables the treatment of a patient on the treatment table at any desired angle without rotating the gantry.
Like with the fully or partially rotating gantry with multiple accelerators, in this instance also the radiation beam from all the accelerators converges at the tumor site simultaneously. It delivers high dose rate radiation to the tumor. When the treatment is rendered with four accelerator combination, it is like the conventional four fields IMRT but with the exception of radiation intensity is modulated by selective beam energies and dose rate as needed for each field and treating all the fields concurrently. If it is an eight accelerators combined radiation therapy system, then it is an eight field synchronous radiation therapy machine. C-band and X-band accelerators are very light weight and very small accelerators. Hence for the eight accelerator combination, the C-band or X-band accelerators are used.
Alternative to a conventional medical linear accelerator, a conventional race track microtron with energies ranging from 4-15 MV electron and mounted within the main stationary gantry or adjacent to it is used as the electron accelerating unit. The electron beam is split by means of electron splitting magnets and guided to each treatment heads by means of guidance and bending magnets to produce electron or photon energies ranging from 4-15 MV as in conventional medical accelerators.
Split Beam from a Race-Track Microtron or a Microtron and its Acceleration in Smaller Waveguides Incorporated Linear Accelerators for a Multiple Linear Accelerators Incorporated Radiation Therapy System
In a racetrack microtron, the initial electron beam from a smaller linear accelerator's waveguide is further accelerated under magnetic force and according to the microtron principles. To make compact multiple medical linear accelerators incorporated into a single radiation therapy system as in this invention, the methods used in racetrack microtron is modified. After a few revolutions of the electron beam in a smaller racetrack microtron, the beam is split into multiple beams and thy are guided into each of the waveguides on the multiple linear accelerator system to increase the energy ranging from 4 to 15 MV or 6-15 MV. Similar split beams are also taken from a simpler microtron but with lesser initial electron beam energy. Because of the electron beam from a single source is conducted to multiple accelerators, the accelerator gantry extension is not feasible and hence only isocentric, SAD method of treatment is feasible in this arrangement of multiple treatment heads incorporated medical accelerator system.